POS0220 THE BIOBEHÇET’S TRIAL: OPTIMAL UTILISATION OF BIOLOGIC DRUGS IN BEHÇET’S DISEASE: A RANDOMISED CONTROLLED TRIAL OF INFLIXIMAB VS ALPHA INTERFERON, WITH GENOTYPING AND METABOLOMIC PROFILING, TOWARDS A STRATIFIED MEDICINES APPROACH TO TREATMENT
Authors: R. Moots, F. Fortune, R. Jackson, T. Thornburn, A. Morgan, D. Carr, P. Murray, G. Wallace, D. Situnayake
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> High-quality randomised trials and predictive biomarkers are required to target therapy optimally in Behçet's syndrome (BS) - especially with high cost biologics. <h3>Objectives</h3> Utilise a Bayesian approach to design and undertake a high quality randomised, head to head, controlled clinical trial of the two most widely used biologics for BS at the time of design of the trial: the anti-TNF infliximab and interferon alpha 2a Roferon and undertake an exploratory analysis of potential predictive biomarkers. <h3>Methods</h3> A pragmatic, prospective, standard of care, single masked, randomised, two arm, parallel head-to-head trial, with the exploratory evaluation of potential biomarkers IFNL3 and IFNL4 SNPs for Roferon, and urinary metabolomics as biomarkers for response to infliximab. Patients with active BS (utilising ISG 1990 classification criteria), with inadequate response to or intolerance of first line treatment were randomised to infliximab (5mg/kg ivi every 6-8 weeks depending on organ involvement) or Roferon (subcutaneous injection: standard tapering dose). Primary outcome: modified Behçet's disease activity index (mBDAI) at 12 weeks of therapy. Secondary outcomes: (a) mBDAI at 24 weeks, (b) significant improvement at 12 and 24 weeks in vitreous haze and best corrected visual acuity change; oral ulcer severity score; number of genital ulcers; arthritis pain; adverse events; reduction in dose of glucocorticoid; Quality of Life and Physician's Global Assessment (disease activity). Sample size was calculated utilising a Bayesian analysis of covariance model (80% credible interval): initial sample size 45/arm (Bayesian power 90%). With anticipated 10% drop-out, recruitment of 100 patients was initially planned. Following recommendations to reduce the overall length of the trial, this was revised down to 80 patients (36/arm allowing for 10% drop out): 80% equi-tailed credibility interval, Bayesian power 88%. A stratified block randomisation scheme was employed, based on randomly permuted blocks, with random block sizes of 2 and 4. Patient follow up was undertaken at weeks 12 and 24, following standard of care. <h3>Results</h3> In this first prospective head-to-head randomised controlled clinic trial of two biologic drugs in BS, infliximab and Roferon were equally effective, with a trend for minor benefit favouring infliximab for tolerability and treatment persistence. Genetic data suggested a potential association between patient outcome and carriage of either rs4803221 or rs7248668 variants in IFNL3 (IL-28B) gene locus in the Roferon-treated arm. However, statistical significance was lost when correcting for multiple testing. Metabolomic analysis identified potential markers for response to treatment with infliximab. <h3>Conclusion</h3> We report an equivalent efficacy between infliximab and Roferon in refractory active BS, better tolerability of Roferon compared to that anticipated, together with the potential for a novel metabolomic biomarkers identifying a clinical response to infliximab. <h3>Acknowledgements</h3> This work was funded by a UK National Institute for Health Research (NIHR) Efficiency and Mechanism Evaluation programme, 12/205 Very Rare Diseases/ EME:12/205/46 Trial Registration: EudraCT: 2014-005390-36; ISRCTN: ISRCTN49793874 <h3>Disclosure of Interests</h3> None Declared.